PROJECT SUMMARY The complexity of central nervous system regulation of energy balance and metabolic homeostasis is underscored by the variety of the signals and brain areas that have been implicated in these homeostatic functions. Within the hypothalamus, the paraventricular nucleus is known to be a critical region involved in the regulation of metabolism and autonomic function. Destruction of the PVH has been associated with hyperphagia, excessive weight gain, alterations in glucose and insulin homeostasis, and cardiovascular function. Although the importance of the PVH in endocrine and autonomic function is widely accepted, relatively little is known about the specific mechanisms through which this heterogeneous group of neurons mediates these effects. This proposal aims to test the hypothesis that discrete subsets of PVH neurons play unique roles in metabolic regulation. We focus on analyzing the neural circuitry, physiologic function and transcriptional profile of insulin receptor substrate-4 neurons located within the PVH. To achieve these goals, a novel IRS4-Cre driver line has been generated. Cre-dependent neuronal tracers and neuron modulators will be injected stereotaxically into the PVH of IRS4-Cre mice to map PVHIRS4 neuronal connections and directly test the role of these neurons in energy balance and metabolic control. Elucidation of the anatomic and cellular mechanisms through which the PVH regulates metabolism and endocrine function will yield new insights and potential targets for the treatment of obesity and diabetes.